Rituximab‐induced serum sickness in immunobullous disorders: A case series

Key Clinical Message Rituximab‐induced serum sickness (RISS) is a rare complication of Rituximab (RTX) in immunobullous disorders. Clinicians should be aware of the occurrence of serum sickness symptoms during RTX administration, and prompt initiation of corticosteroid therapy is crucial in these patients. Additionally, RISS may occur with subsequent RTX doses and patients should be counseled accordingly. Abstract Rituximab (RTX) is a chimeric monoclonal anti‐CD20 antibody which has gained approval for the treatment of various autoimmune and lymphoproliferative disorders. While RTX‐induced minor reactions, including immediate infusion‐related reactions, are common, serum sickness is rare. Limited data exist regarding rituximab‐induced serum sickness (RISS) in pemphigus vulgaris (PV) and mucous membrane pemphigoid (MMP). We report two cases of RISS following RTX administration in PV and MMP patients. Both patients presented with typical symptoms of serum sickness after RTX infusion, necessitating drug cessation and corticosteroid therapy for resolution. RISS represents a rare complication of RTX therapy. Clinicians should maintain awareness of serum sickness presentations during and post‐RTX administration.

severe infection are the most commonly reported late complications. 6,7Serum sickness manifests as a Type III hypersensitivity reaction, mediated by immune complexes, whereby these complexes are deposited on endothelial tissue, instigating an inflammatory cascade that induces symptoms including rash, arthritis, arthralgia, and other systemic manifestations.The onset of this reaction necessitates the confluence of the antigen alongside antibodies specific to it, culminating in the formation of antigen-antibody complexes. 8By producing human anti-chimeric antibodies, RTX causes serum sickness. 9,10Limited data exist about serum sickness in patients with PV and MMP.We report two cases with PV and MMP who developed RISS.

| Case 1
A 42-year-old female presented with vesiculobullous lesions affecting the chest, abdomen, and upper extremities, as well as erosive lesions on lips, oral, and genital mucosa persisting for 8 weeks, culminating in a diagnosis of PV based on histopathology and direct immunofluorescence (DIF).Oral prednisolone 40 mg/day and intravenous RTX infusion were prescribed.
Infusion of 500 mg of RTX in 500 mL of 5% dextrose solution over 4-6 h was done uneventfully after normal results of preliminary investigations.The second infusion was given one week later and no adverse reaction was reported during the infusion.
After 7 days of the second infusion, the patient was referred to the hospital with general malaise, myalgia, and fever along with pain and swelling of small joints of hands as well as both ankles and knees.Physical examination revealed febrile status (T = 38.5 axillary), and tenderness and swelling of the proximal interphalangeal (PIPs), distal interphalangeal (DIPs) joints; and both ankles and knees.No new skin rash or lymphadenopathy was detected.

| Case2
A 35-year-old woman presented with an 11-month history of painful gingival erosions.Despite multiple courses of antibiotic treatment, her lesions continued to worsen.She was referred to our clinic, where we performed punched biopsies for histopathologic and direct immunofluorescent evaluation.Light microscopy revealed a subepidermal blister and a dermal infiltrate composed of lymphocytes, histiocytes, and variable numbers of neutrophils, eosinophils, and plasma cells.Direct immunofluorescence microscopy of normal-appearing perilesional tissue demonstrated linear continuous deposits of IgG, IgA, and C3 at the dermoepidermal junction.Saltsplit skin indirect immunofluorescence revealed IgG, IgA, and C3 binding to both the epidermal and dermal sides of the split.Physical examination did not show involvement of other mucous membranes or the skin.Based on the clinicopathological evaluations the diagnosis of MMP was made and dapsone was initiated at 50 mg daily and titrated up to 100 mg daily.However, after 2 months due to a suboptimal response to Dapsone therapy, RTX was initiated.One week following the first dose of RTX, the patient reported experiencing fever, severe arthralgia, and pruritus morbilliform rashes on her extremities.The patient's symptoms were alleviated after taking analgesics, and she did not report these symptoms during her subsequent visit.
Upon seeking a subsequent dose of RTX without disclosing the prior adverse events, the patient experienced a recurrence of severe arthralgia and myalgia, accompanied by fever and polyarthritis, generalized maculopapular skin rashes, arthritis, and a pulse rate of 110 and respiratory rate of 20.

INVESTIGATIONS, AND TREATMENT
The differential diagnosis of serum sickness includes viral exanthems, urticarial vasculitis, vasculitis, sepsis, and other types of drug reactions.

| Case 1
Laboratory examinations and imaging were conducted, revealing soft tissue swelling on x-rays of the hand joints, elevated C-reactive protein (CRP) and erythrocyte sedimentation rates (ESR) but normal results on complete blood count (CBC), renal function tests, liver function tests, urine analysis, and rheumatological lab tests.
Broad-spectrum antibiotics (intravenous imipenem 500 every 6 h and intravenous vancomycin 1 g twice daily) were initiated due to suspected sepsis.On the sixth day of admission, after stabilizing the patient's condition the third dose of 500 mg RTX was initiated but, after half an hour of starting the infusion, she developed dyspnea, swollen lips, and generalized skin rash.Physical examination revealed tachypnea, tachycardia, and blanchable maculopapular erythematous rash on the trunk, extremities, and face (Figure 1).The infusion was halted, and 100 mg of hydrocortisone was administered intravenously, leading to symptom resolution within approximately 2 h.The patient was diagnosed with a RISS based on the history, physical examination, and excluding other differential diagnoses.She was treated with oral prednisolone 40 mg and analgesic agents for arthritis and myalgia.The platelet count started to decrease from 125,000 to 25,000 platelets per microliter (mcL) (normal range: 150,000-450,000 per mcL) on serial CBCs after the last infusion of RTX.Due to hematologic consultation and normal peripheral blood smear (PBS), the reduction of platelets was attributed to the serum sickness.One week later, she was discharged with advice to avoid RTX in the future.

| Case2
The infusion of RTX was halted, and 100 mg of hydrocortisone was administered.Subsequently, the patient was prescribed oral prednisolone 40 mg and analgesics.Following a four-day hospitalization period, she was discharged in stable condition, with guidance to abstain from further RTX treatment.

| OUTCOME AND FOLLOW-UP
Following an 18-month follow-up period, in Case 1, the patient remained asymptomatic without requiring corticosteroids or corticosteroid-sparing agents.
In Case 2, 40 mg of prednisolone was gradually tapered over a span of 3 months.However, after 1 year, due to a recurrence of oral lesions, prednisolone 30 mg dosage was prescribed again and mycophenolate mofetil was initiated at a dosage of 1 gram twice daily.The prednisolone dosage was further tapered over 8 weeks.The patient is currently on mycophenolate mofetil at a dosage of 1 gram twice daily and prednisolone at 5 mg daily, and her MMP remains controlled.

| DISCUSSION
In this study, we present two cases of RISS in patients with PV and MMP.RTX is an anti-CD-20 antibody that induces cell death through various mechanisms, including complement-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent phagocytosis in CD-20 positive B-cells. 11,12Despite its efficacy, RTX therapy is associated with a spectrum of adverse effects, with serum sickness being a rare but notable complication.Our cases add to the limited data on RISS in PV and MMP patients.
MMP is a heterogeneous type of chronic and autoimmune disorders that are presented as subepithelial blistering involvement of mucous membranes and the skin. 5his treatment, although used off-label, has proven effective in managing moderate to severe cases of MMP. 13 Lamberts et al., evaluated the safety and effectiveness of RTX in patients with recalcitrant pemphigoid.Twentyeight patients with pemphigoid disorders were evaluated.Only one case (the exact subtype of pemphigoid disease was not determined) demonstrated possible symptoms of RISS. 14Based on our knowledge, this is the only reported case of RISS in an MMP patient.
While precise incidence data for RISS are lacking, Karmacharya et al. conducted a systematic review and identified only 33 reported cases, with the majority occurring in patients with rheumatologic diseases, notably Sjögren's syndrome, but none in PV patients.About 50% of cases had a classic triad of serum sickness including arthralgia, rash, and fever. 15Both of our cases had a typical triad of serum sickness.One case developed the symptoms after the first dose and one after the second dose, aligning with the typical onset timeframe reported in the literature.In most cases, including ours (4 out of 5 patients), corticosteroids were the mainstay of treatment for RISS. 15avakolpour et al. systematically reviewed 1085 PV cases treated with RTX over 16 years, finding no instances of RISS, further underscoring its rarity in PV. 6 The majority of RISS occurred in the context of autoimmune diseases rather than malignancies. 16Furthermore, the results of the systematic review and the French National study show that RISS occurs more frequently in people aged 38-37. 15,16able 1 presents the details and comparison of RISS in PV that were reported previously, in addition to the current study.There have been 4 other case reports representing RISS sickness in PV patients. 17,18,21,22The mean age of RISS occurrence in PV cases was 37 ± 12.21 years.All described cases had similar presentations.All reactions happened during the first or second dose of RTX administration, and the dosage of RTX administered was nearly identical.There were no immediate reactions, and all reactions were delayed.
Table 2 shows the clinical symptoms of the RISS patients. 17,18,21,22Polyarthralgia, fever, and skin involvement are the most common symptoms.Less frequent symptoms included lethargy, conjunctivitis, and digestive disorders.RISS symptoms are usually modest and self-limited and the treatment is primarily symptomatic.Serious adverse reactions including glomerulonephritis or neurological sequelae, are rare. 15n the mentioned PV cases, RISS did not result in mortality; however, our patient experienced a hemodynamic collapse episode during the third RTX infusion.In patients with severe presentations, some researchers have recommended using plasmapheresis.However, it is challenging to evaluate the benefits of any treatment without a standard placebo group, especially given that serum sickness typically resolves on its own. 20Due to the reaction that happened in the first series of RTX infusions in the mentioned PV and RISS cases, the history of RISS is not a useful factor for predicting this reaction.RISS may be presented even in patients who received alternative monoclonal Anti-CD20. 19,23In RISS patients, it is so important to advise against re-injection of RTX and educate the patient about this complication.
While rheumatological tests often remain unremarkable in RISS cases, contradicting the autoimmune hypothesis, further research into RISS pathophysiology is warranted. 15hile comprehensive data regarding the relative severity of RISS cases is currently lacking, it appears that akin to other types of serum sickness, the intensity of symptoms is contingent upon dosage.Typically, antigen-antibody complexes are cleared by the mononuclear phagocyte system.However, as the functionality of this system diminishes or becomes inundated by a load of immune complexes, there is a heightened propensity for excessive accumulation of these complexes within the circulation.This culminates in their deposition in tissues or direct formation within affected tissues, consequently precipitating a more pronounced inflammatory reaction. 8wing to the nonspecific symptoms and signs of serum sickness, it can be readily misdiagnosed as other conditions.This was exemplified in our two cases, where the nonspecific nature of the serum sickness symptoms initially led to misattribution to alternative causes.Furthermore, the patient's failure to report these symptoms in subsequent visits resulted in repeated exposure to rituximab infusion.It appears that serum sickness is often underreported due to its indistinct presentation.

F I G U R E 1
Urticarial lesions due to serum sickness in a pemphigus vulgaris patient receiving rituximab.
Details and comparison of RISS among PV cases.
Comparison of the clinical characteristics of serum sickness.
T A B L E 2